دورية أكاديمية
أعرض في EDS

Synthesis and anticonvulsant evaluation of dimethylethanolamine analogues of valproic acid and its tetramethylcyclopropyl analogue.

التفاصيل البيبلوغرافية
العنوان: Synthesis and anticonvulsant evaluation of dimethylethanolamine analogues of valproic acid and its tetramethylcyclopropyl analogue.
المؤلفون: Shekh-Ahmad T; Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel., Bialer M, Yavin E
المصدر: Epilepsy research [Epilepsy Res] 2012 Feb; Vol. 98 (2-3), pp. 238-46. Date of Electronic Publication: 2011 Nov 06.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Publishers Country of Publication: Netherlands NLM ID: 8703089 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-6844 (Electronic) Linking ISSN: 09201211 NLM ISO Abbreviation: Epilepsy Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam : Elsevier Science Publishers, c1987-
مواضيع طبية MeSH: Anticonvulsants/*chemical synthesis , Anticonvulsants/*therapeutic use , Deanol/*chemical synthesis , Deanol/*therapeutic use , Epilepsy/*drug therapy, Animals ; Anticonvulsants/blood ; Anticonvulsants/chemistry ; Brain Waves/drug effects ; Convulsants/toxicity ; Cyclopropanes/pharmacokinetics ; Deanol/blood ; Deanol/chemistry ; Disease Models, Animal ; Electroencephalography ; Electroshock/adverse effects ; Epilepsy/blood ; Epilepsy/chemically induced ; Epilepsy/etiology ; Hippocampus/drug effects ; Hippocampus/physiopathology ; Kindling, Neurologic/drug effects ; Male ; Mice ; Pentylenetetrazole/toxicity ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Valproic Acid/analogs & derivatives
مستخلص: Background: Valproic acid (VPA) is a major antiepileptic drug (AED) that is less potent than other AEDs. 2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA) is an inactive cyclopropyl analogue of VPA that serves as a starting material for the synthesis of CNS-active compounds.
Methods: New conjugation products between N,N'-dimethylethanolamine to VPA and TMCA to form N,N-dimethylethanolamine valproate (DEVA) and N,N-dimethylethanolamine 2,2,3,3-tetramethylcyclopropionate were synthesized and their anticonvulsant activity was assessed in the maximal electroshock seizure (MES) and subcutaneous metrazol (scMet) seizure tests and the hippocampal kindling model in mice and/or rats. An amide analogue of DEVA (DEVAMIDE) was also synthesized and evaluated. The pharmacokinetics of DEVA and DEVAMIDE was comparatively evaluated in rats.
Results: In rats DEVA acted as a prodrug of VPA and had ED(50) values of 73 mg/kg and 158 mg/kg in the MES and the hippocampal kindling models, respectively. At these two anticonvulsant models DEVA was seven-times more potent than VPA. DEVAMIDE was active in the MES test at doses of 100 mg/kg (mice) and its rat-MES-ED(50)=38.6 mg/kg however, its protective index (PI=TD(50)/ED(50)) was twice lower than DEVA's PI. The TMCA analogues were inactive at the mice MES and scMet models. DEVA underwent rapid metabolic hydrolysis to VPA and consequently, in its pharmacokinetic analysis only VPA plasma levels were monitored. In contrast, DEVAMIDE was stable in whole blood.
Conclusion: DEVA acts in rats as a prodrug of VPA yet shows a more potent anticonvulsant activity than VPA. DEVAMIDE acted as the drug on its own and was more potent than DEVA at the rat-MES test.
(Copyright © 2011 Elsevier B.V. All rights reserved.)
المشرفين على المادة: 0 (Anticonvulsants)
0 (Convulsants)
0 (Cyclopropanes)
15641-58-4 (2,2,3,3-tetramethylcyclopropanecarboxylic acid)
2N6K9DRA24 (Deanol)
614OI1Z5WI (Valproic Acid)
WM5Z385K7T (Pentylenetetrazole)
تواريخ الأحداث: Date Created: 20111108 Date Completed: 20120531 Latest Revision: 20131121
رمز التحديث: 20221213
DOI: 10.1016/j.eplepsyres.2011.10.005
PMID: 22057163
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-6844
DOI:10.1016/j.eplepsyres.2011.10.005